Cores for technetium radiopharmaceuticals

ABSTRACT

A  99m Tc complex which contains the moiety Tc═NR, Tc—N═NY or Tc(—N═NY) 2 , and as a synthetic organic ligand which confers biological target-seeking properties on the technetium complex,  
     where:  
     R is an aryl group, a substituted or unsubstituted  
     alkyl group or the group —NR 1 R 2 ;  
     Y is an aryl group or a substituted or unsubstituted alkyl group;  
     R 1  and R 2  are H, aryl groups or substituted or unsubstituted aliphatic or cyclic alkyl groups, and are the same or different provided that both are not hydrogen;  
     where at least one of the R or Y groups comprises an aryl group which chelates the  99m Tc.

[0001] This invention relates to novel complexes of technetium (Tc),containing the moiety Tc═NR, Tc—N═NY or Tc(—N═NY)₂, and their use inradiopharmaceuticals for a variety of clinical applications. Methods forthe preparation of the technetium complexes are also described.

[0002] Radiopharmaceuticals may be used as diagnostic or therapeuticagents by virtue of the physical properties of their constituentradionuclides. Thus, their utility is not based on any pharmacologicaction. Most clinically used drugs of this class are diagnostic agentsincorporating a gamma-emitting nuclide which, because of physical ormetabolic properties of its co-ordinated ligands, localises in aspecific organ after intravenous infection. The resultant images canreflect organ structure or function. These images are obtained by meansof a gamma camera that detects the distribution of ionising radiationemitted by the radioactive molecules. The principal isotope currentlyused in clinical diagnostic nuclear medicine is metastabletechnetium-99m (^(99m)Tc) and which has a half-life of 6 hours.

[0003] The preparation of ^(99m)Tc radiopharmaceuticals generallyrequires addition of generator-produced Na^(99m)TcO₄ eluate to a ligandor ligands in the presence of a reducing agent. Many reducing agentshave been used to this effect including tin metal, stannous ion, sodiumborohydride, ferrous ascorbate, ferrous ion and formamidine sulphonicacid. These procedures often lead to Tc complexes containing the Tc═Omoiety, where the technetium is in the +4 or +5 oxidation state. Theformation of such radiopharmaceutical complexes can often occur viasubstitution reactions on [Tc^(V)OX₅]²⁻ or [Tc^(IV)X₆]²⁻ molecules,which has been identified as a route of significant synthetic utility(Deutsch E, Libson K, Jurisson S, Lindoy L F, Technetium Chemistry andTechnetium Radiopharmaceuticals, Prog. Inorg. Chem. (1982) 30 p 175).Only under harsh reaction conditions in the presence of powerfulreducing agents and/or strong acids or bases are Tc^(I) oxidation statecomplexes attained and stabilised. A limitation to the formation ofnovel radiopharmaceutical products is the tendency towards formation ofTc═O species, but in addition formation of TC⁴⁺ or Tc⁵⁺ complexes alsolimits the number and/or type of ligands prone to bind to the metal.

[0004] PCT Application WO 85/03063 describes the synthesis of the Tc═Nmoiety as an intermediate in the preparation of radiopharmaceuticals byvirtue of its ability to undergo various ligand substitution reactions.The Tc═N core is again primarily based on the +5 oxidation state of Tc.

[0005] The reaction of TcCl₆ ²⁻ with hydroxylamine salts under a varietyof conditions to form a variety of complexes containing the Tc—NO moietyhas been described (Eakins, J C S (1963) 6012; Radnovich and Hoard, J.Phys. Chem. 88 (26) (1984) 6713; Armstrong and Taube, Inorg. Chem.(1976) 15 (3), 1904). This literature is concerned with ⁹⁹Tc and notwith its metastable isotope ^(99m)Tc. ⁹⁹Tc has a half-life of 2.1×10⁵years, decays by emitting beta particles, and is of no interest as aradiopharmaceutical.

[0006] European Patent Application No. 0 291 281 A describes technetiumcomplexes containing the ^(99m)Tc—NO moiety, together with a ligandwhich confers biological target-seeking properties on the complex, andtheir use as radiopharmaceuticals. The complexes are made frompertechnetate (TcO₄ ⁻) by a variety of routes involving hydroxylaminesalts. Studies of the coordination chemistry of technetium havegenerally been directed towards the synthesis and development of new^(99m)Tc labelled radiopharmaceuticals.¹ The majority of the technetiumcontaining radiopharmaceuticals currently in clinical use involvetechnetium complexes containing either a mono-oxo or di-oxo core, i.e.[Tc^(V)═O]³⁺ or [Tc^(V)O₂]⁺ respectively.^(1, 2) Technetium (V)oxo-species are used to image kidney, liver, brain and bone tissues.

[0007] The terminal imido (2−) moiety, ═NR, is formally isoelectronic toa terminal oxo (2−) function, ═O. Many transition metal complexescontaining an organo-imido ligand are known³. Examples include thefollowing complexes based on rhenium ^(4, 5, 6) (I, II), tungsten⁷(III), vanadium⁸ (IV) and molybdenum⁹ (V):

[0008] where Ar is an aryl group.

[0009] When the R substituent of a terminal imide ligand is a dialkylamide moiety, NY₂, the imide ligand is more often described as ahydrazide (2−) ligand. Thus the terminal hydrazido (2−) moiety, ═N—NR₂,is also isoelectronic to a terminal oxo (2−) function, and manytransition metal complexes containing hydrazido (2−) ligands areknown¹⁰. Examples of isostructural metal-oxo and metal-hydrazido (2−)complexes include the following ^(11, 12, 13, 14):

[0010] Similarly, the diazenido moiety, —N═NR, is isoelectronic andisostructural with the nitrosyl ligand (—NO).

[0011] Unlike oxo- and nitrosyl ligands, however, imide (2−), hydrazido(2−) and diazenido ligands can carry a variety of differentsubstitutents on the nitrogen atom which is not bound to the metal atom.The presence of any of these three moieties in a technetium complextherefore permits the preparation of new radiopharmaceuticals with avariety of biological characteristics which can be modulated by varyingor altering the R substituents. In addition, the methods for thesynthesis of complexes containing Tc═NR, Tc═N—NY₂ or Tc—N═NY moietiesare compatible with the concomitant ligation of a wide variety of otherligands. It is this discovery which forms the basis of the presentinvention.

[0012] According to this invention there is provided a complex oftechnetium (⁹⁹Tc or ^(99m)Tc) which contains the moiety Tc═NR, Tc—N═NYor Tc(—N═NY)₂, and a ligand which confers biological target-seekingproperties on the complex,

[0013] wherein

[0014] R represents an aryl group, a substituted or unsubstituted alkylgroup, or the grouping ═NR¹R²;

[0015] Y represents an aryl group or a substituted or unsubstitutedalkyl group;

[0016] and R¹ and R² are hydrogen, aryl groups or substituted orunsubstituted aliphatic or cyclic alkyl groups, and may be both the sameor different, provided that both are not hydrogen.

[0017] The complex is useful as a radiopharmaceutical.

[0018] Complexes in accordance with this invention have the formulae:

L_(n)Tc═NR; L_(n)Tc—N═NY or L_(n)Tc(—N═NY)₂

[0019] wherein

[0020] L represents a mono- or multi-dentate ligand;

[0021] n is 1, 2, 3 or 4

[0022] and R and Y are as defined above.

[0023] The alkyl group substituents may be aliphatic (straight chain orbranched) or cyclic, and may be substituted with, for example, oxygen,nitrogen, sulphur and/or phosphorus.

[0024] A wide range of ligands for these complexes are envisaged,including:

[0025] a) Phosphines and arsines of the general formula Q₂B(CD₂)_(n)BQ₂,where B is P or As; Q is H or aryl or substituted or unsubstitutedalkyl, preferably C1-C4 alkyl or phenyl; n is 1, 2, 3 or 4; and (CD₂) isa substituted or unsubstituted methylene group. Related compounds aredescribed in:

[0026] U.S. Pat. No. 4,481,184, U.S. Pat. No. 4,387,087, U.S. Pat. No.4,489,054, U.S. Pat. No. 4,374,821, U.S. Pat. No. 4,451,450, U.S. Pat.No. 4,526,776, EP-A-0266910 (Amersham International; methylene bridgeddiphosphine complexes), EP-A-0311352 (Amersham International; phosphinescontaining ether groups), and ligands of general type

[0027] R³ _(m)B—(CH₂)_(n)—W—(CH₂)_(n)W—(CH₂)_(n)—BR³ _(m)

[0028] where

[0029] B is P or As,

[0030] W is NR, S, Se, O, P or As,

[0031] R³ is H or hydrocarbon such as C1-C6 alkyl or aryl,

[0032] m is 1 or 2, and

[0033] n is 1, 2, 3 or 4.

[0034] b) Methylene Diphosphonate (MDP)

[0035] c) Thiourea (TU)

[0036] d) Thiomalate (TMA)

[0037] e) Dimercaptosuccinic acid (DMSA)

[0038] f) Gluconate (GLUC)

[0039] g) Ethane-1-hydroxy-1,1-diphosphonate (EHDP)

[0040] h) Diethylene triamine pentaacetic acid (DTPA)

[0041] i) N-(2,6-[Dialkyl]phenyl carbamoylmethyl) iminodiacetate

[0042] alkyl=Methyl (HIDA)

[0043] Ethyl (EHIDA)

[0044]^(i)Propyl (PIPIDA)

[0045] j) Dialkyl dithiocarbamate

[0046] k) Isonitriles of the general type C≡NR⁴

[0047] R⁴=alkyl, alkoxy, ether

[0048] l) BAT Derivatives—of the general type illustrated below, andspecifically:

[0049] i) R⁵═R¹¹═H

[0050]  R^(6,7,9,10)═Et

[0051]  R⁸═N-methylspiropiperidinyl

[0052] ii) R⁵═R¹¹═H

[0053]  R^(6,7,9,10)═Et

[0054]  R⁸═N-ethylspiropiperidinyl

[0055] iii) R⁵═R¹¹═H

[0056]  R^(6,7,9,10)═Et

[0057]  R⁸═N-isopropylspiropiperidinyl

[0058] m) phenanthroline,

[0059] n) pentane-2,4-dione,

[0060] o) bipyridyl,

[0061] p) Other ligands having propylene amine oxime backbone of thegeneral structural types described in EPA 123504 and 194843:

[0062] q) Bisthiosemicarbazones of the formula:

[0063] where the various groups R¹² can be the same or different and areH and/or alkyl and/or aryl substituents. Other suitable ligands areshown in Table 1.

[0064] The invention further provides methods for the preparation of theaforementioned complexes of technetium. One such method involves thederivatisation of technetium oxo-containing species by condensation withhydrazines or amines (equation A), isocyanates (equation B)sulphinylamines (equation C) or phosphinimines (equation D):

[0065] A: L_(n)Tc═O+H₂NR →L_(n)Tc═NR+H₂O

[0066] B: L_(n)Tc═O+OCNR→L_(n)Tc═NR+CO₂

[0067] C: L_(n)Tc═O+OSNR→L_(n)Tc═NR+SO₂

[0068] D: L_(n)Tc═O+Ph₃P═NR→L_(n)Tc═NR+Ph₃P═O

[0069] wherein R, L and n are defined as above. The driving force forthese reactions is the formation of a stable product containing theformer oxo function (i.e. water, carbon dioxide, sulphur dioxide orphosphine oxide), which is generally easily removed after the oxo grouptransfer, leaving the desired technetium hydrazido (2−) or imidocomplex.

[0070] An alternative method of preparation involves the reaction ofhydrazines (equation E) or amines (either aliphatic or aromatic)(equation F) with complexes containing technetium-halogen bonds:

[0071] E: L_(n)Tc Cl₂+H₂NNR¹R²→L_(n)Tc ═NNR¹R²+2HCl

[0072] F: L_(n)Tc Cl₂+H₂NR→L_(n)Tc═NR+2HCl

[0073] where L, R, R¹ and R² are as previously defined.

[0074] The driving force for these reactions is the concomitantformation of the volatile, easily removed hydrogen halide during themetathesis reaction.

[0075] It will be appreciated that the hydrazides and diazenides can beconsidered as essentially being functionalised imide ligands. Thehydrazide (2−) ligand, ═NNR¹R², is just the imide ligand, ═NR, where Ris NR¹R²; and the diazenide ligand results when R₁ is hydrogen. In thiscase, the intermediate hydrazide (2−) complex is deprotonated by a baseto give a metal-diazenide complex with concomitant reduction of themetal centre:

[0076] In the reactions reported herein, the base is always the addedexcess of hydrazine in the solution.

[0077] Turning now to the preparation of the technetium complexescontaining an imido moiety, the approach has been to replace the oxofunction in [TcOX₄]⁻ (X═Cl, Br) using arylisocyanates (reaction typeequation B). This formed a convenient entry point into the work byextending an established route for the synthesis of Tc═NR complexes.This method has only been previously used for generation of neutralimido products from neutral transition metal oxo starting materials.¹⁷The work reported here is thus the first example of the method extendedto the preparation of anionic transition metal imido complexes, and alsoto technetium chemistry.

[0078] Reaction of [Tc^(V)OX₄]⁻ with excess ArNCO in refluxing drytoluene under nitrogen gives excellent yields of the desiredTc^(V)-imido products isolated as solids on ether trituration of theresidue obtained directly from the reaction mixture (equation G):

[0079] Even though the method gives good yields of reasonably puresolids, the reaction is not trivial. The starting isocyanates are quitemoisture and air sensitive such that the reaction must be strictlyperformed under an atmosphere of N₂. 1 and 2 are black-blue solids thatare also quite sensitive to adventitious moisture, however, they arestable under dry N₂. That the products are very sensitive to moisture isevidenced by the fact that if reagent grade diethyl ether is used in thetrituration phase of the workup procedure instead of anhydrous ether,then the product is isolated as a red-brown insoluble polymericcompound. The products also do not always chromatograph (HPLC)satisfactorily.

[0080] The products [Tc(Ntol)X₄]⁻ contain the new core moiety[Tc^(V)═NR]³⁺ which is formally analogous to the well known [Tc═O]³⁺core. [Tc(NR)X₄]⁻ is a sixteen electron species in which the imidoligand functions as a four electron donor; the technetium-nitrogen bondis therefore expected to be a short, linear multiple [Tc═NR] bond.Attempted structural characterisation of [Tc(Ntol)Cl₄]⁻ as its PPh₄ ⁺salt by X-ray crystallography has so far been unsuccessful due to itssensitive nature. The products 1 and 2 are very good starting materialsfor the preparation of many new Tc═NR complexes.

[0081] In view of the somewhat sensitive nature of 1 and 2,investigation of much more stable Tc-imido complexes was undertaken. Thedirect metathesis reactions of [TcOCl₄]⁻ with aromatic amines wasundertaken in the presence of phosphine ligands. Reactions of this typemay show promise in ^(99m)Tc chemistry in view of the wide variety ofsubstituted aromatic amines available commercially.

[0082] Reaction of [TcOCl₄]⁻ with ArNH₂ in refluxing MeOH in thepresence of the monodentate phosphine PPh₃ gives the green-brown neutralTc^(V) imido complexes which analyse for [Tc(NR)Cl₃(PPh₃)₂] (equationH):

[0083] Chromatographic analysis (HPLC, beta detection) of these productsshow only one significant ⁹⁹Tc-containing species. These neutral Tc^(V)complexes also contain the new [Tc^(V)═NR]³⁺ core. They are diamagnetic,air-stable solids which are very soluble in CH₂Cl₂, CHCl₃, moderatelysoluble in alcohols, and insoluble in ether and petrol. They exhibit asinglet (ca. 30 ppm) in the ³¹P NMR spectrum, indicating two trans-PPh₃groups in identical environments. Structural characterisation of 3 byX-ray has now been carried out and FIG. 1 gives a Ball and Stickrepresentation of the complex molecule. The diagram shows a lineartolylimide group and the two PPh₃ groups to be trans. The [Tc═Ntol] unitin 3 may therefore be correctly assigned as a linear four electron donorimido ligand, and the complex is formally an 18-electron species.

[0084] This work therefore represents the first structurallycharacterised Tc^(V)-imido complex.

[0085] The [Tc(NR)Cl₃(PPh₃)₂] compounds are much superior startingmaterials than [Tc(NR)X₄]⁻ because these are much more stable Tc═NRspecies.

[0086] Reaction of [TcOCl₄]⁻ with excess amine and dppe in refluxingMeOH or EtOH allows the isolation of good yields of the cationicTc-imido complexes [Tc^(IV)(NC₆H₄Z)Cl-(dppe)₂]⁺ as their BPh₄ ⁻ salts(equation 1):-

[0087] 1: (Bu₄N) [TcOCl₄]+excess ZC₆H₄NH₂+excess dppe

[0088] 6 Z═CH₃, 60%, violet

[0089] 7 Z═Br, 64%, maroon

[0090] 8 Z═Cl, 64%, maroon

[0091] These complexes 6, 7, and 8 are all air-stable darkly colouredcationic Tc^(IV)-imido complexes. Chromatographic analysis (HPLC, betadetection) indicates single ⁹⁹Tc-containing species. They are quitesoluble in CH₂Cl₂ and insoluble in ether, petrol and alcohols. They maybe conveniently recrystallised from CH₂Cl₂/MeOH.

[0092] Their assignment as Tc(IV) complexes is from the followingcharacterisation: The analysis stoichiometry fits the formula[Tc(NR)Cl(dppe)₂](BPh₄). Although Γ Tc═N is not assignable there is noevidence for Γ NH in the infrared. The compounds exhibit very broadenedNMR spectra (¹H, ³¹P) at room temperature which are not easily assigned.They are assumed to be paramagnetic Tc^(IV) imido complexes and notTc^(III)-amido (TcNHR) complexes on this basis.

[0093] This represents another new core, the [Tc^(IV) = NR]^(2 + IV)

[0094] moiety. Evidence for the existence of this new Tc core comes fromthe structural characterisation of a [Tc^(IV)-hydrazido(2−)bis(dppe)Cl]⁺cation which contains a [Tc^(IV)NNR₂]²⁺ core¹⁸. Hydrazido(2−) andimido(2−) are formally analogous. Further evidence comes from theexistence and relative stability of the analogous [Tc^(IV)═O]²⁺ corefrom the electrochemical reduction of some Tc^(V) oxo Schiff basecomplexes¹⁹.

[0095] It is to be understood that reactions of the aforementioned typeA-F are well known for the synthesis of various transition metalhydrazido (2−) and imido complexes^(3, 10). While it is believed thatthey have not previously been used for the production of technetiumcomplexes of the kind described and claimed herein, it is acknowledgedthat the synthesis of technetium-nitride complexes using hydrazinehydrochloride itself has already been reported^(15, 16).

[0096] Using the approach of equation A above, the reactions ofhydrazines with [NBu₄][TcOCl₄] were studied, and the intermediateproducts further functionalised with mono- or bi-dentate ligands. Inparticular, the reaction of complexes containing technetium-oxo moieties[Tc═O] with mono-substituted hydrazines or 1,1-disubstituted hydrazinesproduces technetium-diazenide or technetium-hydrazide (2−) species.

[0097] The facile synthesis of [TcCl(NNPh)₂(PPh₃)₂] from [Bu₄N][TcOCl₄],PhNHNH₂, and PPh₃ in methanol under reflux has been demonstrated²⁵. Thiscomplex proved to be somewhat insoluble and could not be satisfactorilyrecrystallised due to its poor solubility. This unsubstitutedphenyl-diazenido-complex thus appears to be polymeric, possiblycontaining chloro-bridges. Consequently it was not thought to be asuitable starting material for investigation of substitution chemistry.

[0098] Use of 4-substituted hydrazine hydrochlorides 4—XC₆H₄NHNH₂.HCl(X═Cl, CH₃) has lead to the preparation of the analogousbisdiazenido-complexes [TcCl(NNC₆H₄X)₂(PPh₃)₂] (X═Cl, 9; X═CH₃, 10).These air-stable orange crystalline solids are reasonably solublecompounds and are much superior starting materials. Complex 9 (X═Cl) inparticular has proved to be the most suitable for a systematicinvestigation of the substitution chemistry of the technetium bisdiazenido-complexes, giving relatively clean products on reaction withthe appropriate ligand.

[0099] A most important development in this work is the fact that thesediazenido-complexes [TcCl(NNR)₂(PPh₃)₂] may also be synthesised directlyfrom [TcO₄]⁻. Reaction of [NH₄][TcO₄] with ClC₆H₄NHNH₂.HCl and PPh₃ indry methanol under reflux gives a good (60-70%) yield of[TcCl(NNC₆H₄Cl)₂(PPh₃)₂] 9. Many variations in experimental conditionswere tried. The best method is reported here. This result suggests thatall technetium diazenido-complexes may be synthesised in good yielddirectly from [TcO₄]⁻.

[0100] In order to investigate which complexes could be synthesiseddirectly from [TcO₄]⁻ in future work, it has been important todemonstrate that the diazenido- (and imido-) cores may be incorporatedinto a wide variety of complex types. For diazenido-cores this hasmainly been approached by the systematic substitution of 9.

[0101] Reaction of 9 with excess dppe in methanol under reflux givespure [TcCl(NNC₆H₄Cl)(dppe)₂]⁺, 12 isolated as orange crystalline BPh₄ ⁻or PF₆ ⁻ salts in good yield. Complexes of this type may also beprepared directly from [NH₄][TcO₄].

[0102] Reaction of 9 with dmpe under similar conditions leads to theisolation of a pale-pink cationic solid (HPLC retention time 10 minutes,single species) containing no nitrogen. This product could not beisolated in pure form, but is tentatively formulated as[Tc^(I)(dmpe)₃][BPh₄]. The analogous reaction under less forcingconditions at room temperature leads to the desired cation[TcCl(NNC₆H₄Cl)(dmpe)₂]⁺ isolated as its PF₆ ⁻ salt (HPLC retention time9.6 minutes, single species).

[0103] In order to elucidate the validity of both [Tc(N₂Ar)₂]⁺ and[Tc(N₂Ar)]²⁺ as new cores for the development of Tc-basedradiopharmaceutical products it was necessary to investigate thelability of the —N₂Ar unit on reaction with other ligands. Detailed HPLCexperiments (beta detection) were performed to see if a bisdiazenido-intermediate was formed in the preparation of the cation 12(retention time 14 minutes) from the starting material 9 (retention time9.4 minutes). The HPLC results showed that the cation formed after only15 minutes stirring at room temperature and that no other Tc-containingintermediate was detected. This proves that one —N₂Ar moiety is verylabile, and is easily lost in solution at room temperature in thepresence of the appropriate ligand to give the monodiazenido-product.

[0104] Reaction of 9 and 10 with the less bulky phosphines (PMe₂Ph,PMePh₂) gave single species in solution (HPLC). However, the highsolubility precluded further workup of these apparently cationicproducts. Reaction of [Bu₄N][TcOCl₄], XC₆H₄NHNH₂.HCl (X═Cl, CH₃) and theappropriate phosphine also leads to isolation of these solutions (HPLC).

[0105] Reaction of the commercially available hydrazine O₂NC₆H₄NHNH₂with [Bu₄N][TcOCl₄] and PPh₃ in methanol leads to the isolation of thelime-green Tc(III) monodiazenido-complex [TcCl₂(NNC₆H₄NO₂)(PPh₃)₂], 11in reasonable yield. Apparently a bis diazenido-complex is not Formedfrom reaction of this nitro-substituted phenylhydrazine. The complex 11promises to be a useful starting material for the preparation of avariety of monodiazenido-complexes as it has two easily replaceablechlorides. In the presence of dppe in methanol-toluene under refluxcomplex 11 gives orange [TcCl(NNC₆H₄NO₂)(dppe)₂]⁺ , 13 isolated as itsBPh₄ ⁻ salt in good yield. [TcCl(NNC₆H₄NO₂)(dmpe)₂][PF₆] (retention time10 minutes, single species) was prepared in high yield directly from[TcOCl₄]⁻, the hydrazine, and dmpe in refluxing methanol-toluene.

[0106] Reaction of 9 with sodium dimethyldithiocarbamate in absoluteethanol under reflux gives the novel orange Tc(III) diazenido-complex[Tc(NNC₆H₄Cl) (S₂CNMe₂)₂(PPh₃)], 14 in reasonable (66%) yield. Complex14 is air-stable both in the solid state and in solution.Recrystallisation from CH₂Cl₂/Et₂O gives X-ray quality orange crystals.Satisfactory elemental analysis and spectroscopic data suggest theformulation to be correct. The room temperature ¹H NMR spectrum of 14 isindicative of its coordination geometry. The four methyl groups in 14appear as four sharp singlets. This resonance pattern shows that the twodithiocarbamato ligands are non-equivalent, and is consistent with acis-conformation. This has to be confirmed by X-ray structure analysis.If the dithiocarbamato ligands were trans- and the four methyl groupsthus equivalent, the ¹H spectrum would show a single resonance whichwould not be expected to change with temperature.

[0107] Reaction of 9 with maltol gives a dark-orange crystallinecompound. This is a single species (HPLC) and analyses as[TcCl(NNC₆H₄Cl)(maltol) (PPh₃)₂], 15. This novel Tc(III) diazenidocomplex is formally analogous to the structurally characterised[ReCl(NNCOPh)(maltol)(PPh)₃)₂]²⁶, and is the first reported Tc complexcontaining the maltol ligand.

[0108] Reaction of 9 with the tetradentate N₂O₂ (2−) ligand salenH₂ inmethanol-toluene under reflux in the presence of Et₃N gives the neutraldark-green Tc(III) diazenido-complex [Tc(NNC₆H₄Cl)(salen)(PPh₃)], 16 ingood yield. Similar reaction of 9 with the obligately planartetradentate N₂O₂(2−) ligand salphenH₂ gave no well defined productsuggesting that a cis-geometry of the —N₂Ar and PPh₃ groups ispreferred. Further evidence for a preferred cis-geometry is suggestedfrom the spectroscopic results of 14. This is expected to be confirmedby X-ray structure analysis.

[0109] Reaction of 9 with the N₂S₂ ligand (HSCH(Me)CONHCH₂—)₂ in thepresence of Et₃N gave a dark-brown solid. The product was too insolublefor satisfactory analysis by NMR, but appeared to be diamagnetic.Elemental analysis on the product isolated directly from the reactionmixture suggested the formulation as a bis diazenido-complex[Tc(NNC₆H₄Cl)²⁻ (SCH(Me)CONHCH₂CH₂NHCOCH(Me)S)]_(x), 17.

[0110] Much effort has been directed to the development of a syntheticroute to Tc imido-complexes directly from [TcO₄]⁻. Reaction of aqueousmethanolic solutions of [TcO₄]⁻ with aromatic amine and PPh in thepresence of concentrated HCl gives only low yields of the desired Tc(V)imido-complexes [TcCl₃(NAr)(PPh₃)₂)]. These complexes have been preparedpreviously from [Bu₄N][TcOCl₄].²⁵ The nature of the reaction from[TcO₄]⁻ appears to be very dependent on the concentration of HCl used.Use of excess HCl gives [TcCl₄(PPh₃)₂].

[0111] The use of amine hydrochloride (ArNH₃Cl) as an alternative to theaddition of HCl in this reaction has also been investigated in somedetail. [TcO₄]⁻ reacts with ArNH₃Cl and PPh₃ in aqueous methanol to givea bright blue, neutral product in high yield after about 20 minutesstirring at room temperature. This product appears to be independent ofthe aromatic amine hydrochloride used. The blue compound appears to bediamagnetic (NMR) and shows evidence for coordinated PPh₃, but containsno nitrogen. This compound analyses reasonably as [Tc₂Cl₄(PPh₃)₄] whichis analogous to many known Re—Re multiply bonded species. Use ofaliphatic amine hydrochlorides (RNH₃Cl) leads to rapid conversion toblack insoluble “TcO₂.xH₂O”.

[0112] Reaction of [NH₄][TcO₄] with the hydrochloride of anthranilicacid (2—HO₂CC₆H₄NH₃Cl) under analogous conditions gives a lime-greenprecipitate. This analyses reasonably well as [TcCl₂(NC₆H₄CO₂)(PPh₃)₂],18 and is expected to have the novel structure containing a bent TcNCframework. The bent chelating imidobenzoate (3−) ligand is thus a newcore moiety for technetium. The complex 18 may also be prepared from[TcOCl₄]⁻ in lower yield. Anthranilic acid is known to react with[ReOCl₃(PPh₃)₂] in ethanol to give the chelating imidobenzoate (3−)complex [ReCl(OEt)(NC₆H₄CO₃)(PPh₃)₂].²⁷

[0113] This is a manor development as it suggests that imido-complexesare more generally accessible from [TcO₄]⁻. The chelate effect must insome way stabilise the formation of this imido-ligand. The establishmentof a conjugation pathway through the M═N, C═C, and C═O may be a drivingforce for its formation. The reaction of [TcO₄]⁻ and anthranilic acidhydrochoride in the presence of a wide variety of non-phosphine ligandsis envisaged.

[0114] Much effort has been directed to synthesis of Tc imido-ligandsfrom [TcO₄]⁻ using the hydrazines RCONHNHAr (R═CH₃, Ph), and also theirhydrochlorides as a source of the NAr ligand. Use of the symmetricallysubstituted hydrazines RNHHNR (R═Me, Et, PhCO, Ph) is also envisaged.Preliminary experiments for both [TcO₄]⁻ and [TcOCl₄]⁻ have shown thatmixtures of products are being formed (HPLC).

[0115] Our work has resulted in the synthesis of two new classes oftechnetium complexes with hydrazido (2−), i.e. ⁼NNR₂, and diazenido,i.e. —NNR, substituents, at both the carrier added (⁹⁹Tc) and the nocarrier added (^(99m)Tc) levels. Both neutral and cationic derivativeshave been prepared within each class. These complexes are useful asradiopharmaceuticals and thus provide a new range of such reagents.

[0116] Specifically, the following new complexes containing hydrazido(2−) and diazenido moieties have been prepared:

[0117]⁹⁹Tc: Carrier Added Level

[0118] [Tc^(V)(NNMePh)Cl₃(PPh₃)₂]

[0119] [Tc^(V)(NNMePh)Cl₂(PMe₂Ph)₃][PF₆]

[0120] [Tc^(V)(NNMePh)Cl(Et₂NCS₂)₂]

[0121] [Tc(N₂)Cl(dppe)₂]

[0122] [Tc^(IV)(NNMe₂)Cl(dppe)₂][PF₆]

[0123] [Tc^(V)O(NH)dppe][PF₆]

[0124] [Tc^(III)(NNPh)₂Cl(PPh₃)₂]

[0125] [Tc^(III)(NNPh)Cl(dppe)₂][PF₆]

[0126] [Tc(NNC₆H₄Cl)Cl(dppe)₂)[PF₆]

[0127] [Bu₄N][Tc(NC₆H₄CH₃)Br₄], [Bu₄N][Tc(NC₆H₄C₃)Cl₄], Tc

[0128] (NC₆H₄Z)Cl₃(PPh₃)₂, where Z ═CH₃, Br, Cl,

[0129] [Tc(NC₆H₄Z)Cl(dppe)₂][BPh₄], where Z is as above.

[0130]^(99m)Tc: No-Carrier Added Level*

[0131] [Tc^(III)(NNPh)Cl(L)₂]⁺

[0132] L=dmpe, dppe, P46, P53, P56, P68, PL28, PL31, PL34, PL37, PL38,PL40, PL42, L43, PL46, PL49, PL50.

[0133] [Tc^(III)(NNC₆H₄NO₂)Cl(L)₂]⁺

[0134] L=dmpe

[0135] [Tc^(IV)(NNMePh)Cl(L)₂]⁺

[0136] L═dmpe, P34, P46, P53, P65, P68, PL28, PL38

[0137] *The structures of the ligands, L, given here are shown in Table1.

[0138] Of these, animal biodistribution data has been obtained for thefollowing ^(99m)Tc species and the results are shown in Tables 2, 3 and4:

[0139] [Tc^(III)(NNPh)Cl(L)₂]⁺

[0140] L═dmpe, PL28, P46, PL42, PL43, P65, PL50, PL38 (Table 2)

[0141] [Tc^(III)(NNC₆H₄NO₂)Cl(L)₂]⁺

[0142] L=dmpe (Table 3)

[0143] [Tc^(IV)(NNMePh)Cl(L)₂]⁺

[0144] L=dmpe, P46, P65 (Table 4)

[0145] This invention will now be further illustrated by the followingExamples:

[0146]⁹⁹Tc Complexes

[0147] All reactions were performed under an atmosphere of nitrogenusing predried, distilled solvents unless noted otherwise. [NBu₄][TcOCl]was prepared by the literature procedure²⁰. All other reagents used wereobtained from commercial sources and used as received. Aqueous solutionsof [NH₄][TcO₄] were obtained from Amersham International plc.

[0148] All complexes were characterised by elemental analysis. IR, ¹HNMR and ³¹P NMR. Only analytical data are included here butspectroscopic information is available. In addition to the abovephysical characterisation of the complexes single crystal X-raystructures have been obtained for four complexes:[Tc(NNPh)Cl(dppe)₂][PF₆], [Tc(NH)O(dppe)₂][PF₆], [Tc(NNME₂ )Cl(dppe)₂][PF₆] and Tc(NC₆H₄CH₃)Cl₃(PPh₃ )₂.

EXAMPLE 1

[0149] Reaction of (Bu₄N) (TcOX₄) (X═Cl, Br) with 4-Tolyl-isocyanate

[0150] i) Tetrabutylammonium(1+)tetrachloro(p-tolylimido) technetate (V)(1−), (Bu₄N) [Tc(Ntol)Cl₄]1

[0151] (Bu₄N) [TcOCl₄] (0.194 g, 0.39 mmol) was suspended in drydegassed toluene (10 ml) and MePhNCO (0.25 ml, 1.98 mmol, 5 equivalents)was added. The mixture was then vigorously refluxed under N₂ for 45minutes. After cooling to room temperature the toluene was decanted off,and the black residue was triturated with dry diethyl ether (10 ml)before collection of the blue-black solid 1 by filtration. On washingthoroughly with diethyl ether the product was dried in vacuo. (Yield0.229 g, 0.39 mmol, 100%). In similar preparations of 1 the yield wasnever less than 95% and therefore the conversion was considered to beessentially quantitative. (Found: C, 49.31; H, 7.22; N, 5.02. calc forTcC₂₃H₄₃N₂Cl₄: C, 47.03; H, 7.37; N, 4.77%); ¹H NMR (d₆-DMSO) 0.9[12H,broad unresolved triplet, (CH₃(CH₂)₃)₄N]; 1.4[24H, broad multiplet,(CH₃(CH₂)₃)₄N]; 2.2[3H, singlet, C₃C₆H₄N—Tc]; 7.0-7.4[4H, multiplet,CH₃C₆H₄NTc]; v_(max). (Nujol mull, KBr plates) 1170 m br cm⁻¹ (Tc═N,tentative assignment).

[0152] ii) Tetrabutylammonium(1+)tetrabromo(p-tolylimido) technetate (V)(1−), (Bu₄N) [Tc(Ntol)Br₄]2

[0153] The blue-black product 2 was prepared an a similar fashion to 1using (Bu₄N) [TcOBr₄] (0.268 g, 0.396 mmol) and MePhNCO (0.25 ml, 1.98mmol, 5 equivalents) in refluxing dry toluene (15 ml). (Yield 0.224 g,0.29 mmol, 74%). HPLC retention time 9.6 minutes, single species;(Found: C, 36.73; H, 6.43; N, 3.16. calc for TcC₂₃H₄₃N₂Br₄: C, 36.10; H,5.66; N, 3.66%); ¹H NMR (CDCl₃) 1.0[12H, broad unresolved triplet,(CH₃(CH₂)₃)₄N]; 1.5[24H, broad multiplet, (CH₃(CH₂)₃)₄N]; 2.27[3H,singlet, CH₃C₆H₄NTc]; 6.9-7.5[4H, multiplet, CH₃C₆H₄NTc]; v_(max).(Nujol mull, KBr plates) 1175 cm⁻¹ (Tc═N, tentative assignment).

EXAMPLE 2

[0154] Reactions of (Bu₄N) [TcOCl₄] with Aromatic Amines (4-ZC₆H₄NH₂,Z═CH₃, Br, Cl) in the Presence of Triphenylphosphine, PPh₃

[0155] i) Trichloro(p-tolylimido)bis(triphenylphosphine) technetium (V),Tc(NC₆H₄Z)Cl₃(PPh₃)₂ Z═CH₃, 3

[0156] (Bu₄N) [TcOCl₄] (0.216 g, 0.43 mmol), CH₃C₆H₄NH₂ (0.07 g, 0.65mmol, 1.5 equivalents) and PPh₃ (0.34 g, 1.3 mmol, 3 equivalents) wererefluxed in dry methanol (10 ml) under N₂ for 40 minutes. After coolingto room temperature, the brown-green mixture was evaporated to 5 ml, anddiethyl ether (15 ml) was added to aid precipitation of 3. Thegreen-brown product was collected by filtration, washed thoroughly withether and dried. The product could be recrystallised from CH₂Cl₂/hexanemixture. (Yield 0.094 g, 0.11 mmol, 26%). HPLC retention time 10.8minutes, single species; (Found: C, 59.01; H, 4.35; N, 1.76; Cl, 12.80.calc for TcC₄₃H₃₇NCl₃P₂: C, 61.84; H, 4.46; N, 1.68; Cl, 12.74%); ¹H NMR(CDCl₃) 2.2[3H, s, CH₃C₆H₄NTc]; 6.5-6.8[4H, m, CH₃C₆H₄NTc]; 7.0-8.0[30H, m, phenyl H]. There was no evidence of NH in the proton spectrum;⁻P-(¹H) NMR (CDCl₃) 30.02 s ppm; v_(max). (Nujol mull, KBr plates) 1165cm⁻¹ (Tc═N, tentative assignment). There were no absorptions which couldbe attributed to ^(v)NH.

[0157] ii) Trichloro(p-bromophenylimido)bis (triphenylphosphine)technetium (V), Tc(NC₆H₄Z)Cl₃(PPh₃)₂ Z═Br, 4

[0158] (Bu₄N) [TcOCl₄] (0.210 g, 0.42 mmol), BrC₆H₄NH₂ (0.11 g, 0.64mmol, 1.5 equivalents) and PPh₃ (0.331 g, 1.26 mmol, 3 equivalents) wererefluxed in dry methanol (10 ml) to give on workup and recrystallisationfrom CH₂Cl₂/hexane a very low yield of brown solid 4. (Yield 0.052 g,0.06 mmol, 14%). HPLC retention time 9.6 minutes, single species;(Found: C, 54.38; H, 4.00; N, 1.53; Cl, 10.56. calc forTcC₄₂H₃₄NP₂Cl₃Br: C, 56.05; H, 3.81; H, 1.56; Cl, 11.82. calc forTcC₄₂H₃₄NP₂Cl₃Br. ½ CH₂Cl₂C, 54.45; H, 3.72; N, 1.48; Cl, 14.95%); ¹HNMR (CDCl₃) 5.25[s, CH₂Cl₂]; 6.8[4H, m, BrC₆H₄NTc]; 7.0-8.0[30H, m,phenyl H]; ³¹P-{¹H} NMR (CDCl₃) 29.93 s ppm; v_(max). (Nujol mull, KBrplates) 1165 cm⁻¹ (Tc═N, tentative assignment).

[0159] iii) Trichloro(p-chlorophenylimido)bis(triphenylphosphine)technetium (V), TC(NC₆H₄Z)Cl₃(PPh₃)₂ Z═Cl, 5

[0160] (Bu₄N) [TcOCl₄] (0.272 g, 0.545 mmol), ClC₆H₄NH₂ (0.104 g, 0.82mmol, 1.5 equivalents) and PPh₃ (0.43 g, 1.64 mmol, 3 equivalents) wererefluxed in dry methanol (10 ml) to give a very low yield of brown solid5. (Yield 0.084 g, 0.098 mmol, 18%). HPLC retention time 9.2 minutes,single species; (Found: C, 55.85; H, 3.86; N, 1.63. calc forTcC₄₂H₃₄NP₂Cl₂: C, 58.96; H, 4.00; N, 1.64%); ¹H NMR (CDCl₃) 6.5-6.7[4H,m, ClC₆H₄NTc]; 7.0-8.0[30H, m, phenyl H]; ⁻P-(¹H) NMR (CDCl₃) 29.87 sppm; v_(max). (Nujol mull, KBr plates) 1170 cm⁻¹ (Tc═N, tentativeassignment.

EXAMPLE 3

[0161] Reactions of (Bu₄N) [TcOCl₄] with Aromatic Amines (4-ZC₆H₄NH₂,Z═CH₃, Br, Cl) in the Presence of Bis(diphenylphosphino)ethane, dppe

[0162] l) [Tc(NC₆H₄Z)Cl(dppe)₂](BPh₄) Z═CH₃, 6

[0163] (Bu₄N) [TcOCl₄] (0.333 g, 0.67 mmol), CH₃C₆H₄NH₂ (0.36 g, 3.33mmol, 5 equivalents), and dppe (0.80 g, 2.0 mmol, 3 equivalents) in drydegassed methanol (20 ml) were refluxed for 1 hour. After cooling toroom temperature, the violet mixture was filtered into a clean flask toremove some insoluble red material. Sodium tetraphenylborate (0.23 g,0.67 mmol) in methanol (5 ml) was added with stirring to immediatelyprecipitate out a copious amount of violet solid 6. The product wascollected by filtration and washed thoroughly with MeOH, and then ether.The product could be recrystallised from CH₂Cl₂/MeOH or CH₂Cl₂/hexane.(Yield 0.544 g, 0.40 mmol, 60%). HPLC retention time 8.4 minutes, onemajor species; (Found: C, 74.09; H, 7.09; N, 1.70; Cl, 3.22. calc forTcC₈₃H₇₅NClP₄B: C, 73.54; H, 5.58; N, 1.03; Cl, 2.62%).

[0164] There are no infrared absorptions assignable to NH stretches, andthe ^(v)Tc═N stretch could not be assigned unambiguously. The productgave a broadened ¹H NMR spectrum and was assumed to be paramagneticTc(IV). The ³¹P NMR spectrum also showed broadened resonances.

[0165] If less ArNH₂ was used in the reaction a red precipitate believedto be [Tc^(III)Cl₂(dppe)₂]Cl forms in approximately 50% yield from theMeOH on cooling to room temperature.

[0166] ii) [Tc(NC₆H₄Z)Cl(dppe)₂)(BPh₄) Z═Br, 7

[0167] (Bu₄N) [TcOCl₄] (0.179 g, 0.36 mmol), BrC₆H₄NH₂ (0.31 g, 1.79mmol, 5 equivalents) and dppe (0.429 g, 1.08 mmol, 3 equivalents) wererefluxed in dry methanol (10 ml, 1 hour). NaBPh₄ (0.122 g, 0.36 mmol) inMeOH (5 ml) was added to the cooled filtered reaction mixture withstirring to isolate 7 as a maroon solid on filtration. (Yield 0.325 g,0.23 mmol, 64%). HPLC retention time 7.6 minutes, one major species.Analysis on the crude material gave (Found: C, 73.19; H, 5.91; N, 0.89;Cl, 3.19. calc for TcC₈₂H₇₂NBrClP₄B: C, 69.33; H, 5.11; N, 0.99; Cl,2.50%) and suggests contamination with BPh₄ ⁻ or Cl⁻. The product couldbe recrystallised from CH₂Cl₂/MeOH.

[0168] iii) [Tc(NC₆H₄Z)Cl(dppe)₂](BPh₄) Z═Cl, 8

[0169] (Bu₄N) [TcOCl₄] (0.28 g, 0.56 mmol), ClC₆H₄NH₂ (0.358 g, 2.8mmol, 5 equivalents) and dppe (0.67 g, 1.68 mmol, 3 equivalents) wererefluxed in dry methanol (15 ml, 75 minutes). NaBPh₄ (0.19 g, 0.56 mmol)in MeOH (5 ml) was added to the cooled filtered reaction mixture withstirring to precipitate out the dark maroon solid 8 which was collectedby filtration. (Yield 0.497 g, 0.36 mmol, 64%). HPLC retention time 8.0minutes, one major species. Analysis on the crude material gave (Found:C, 73.56; H, 5.94; N, 1.72; Cl, 3.26. calc for TcC₈₂H₇₂NCl₂P₄B: C,71.57; H, 5.27; N, 1.02; Cl, 5.15%) and suggests contamination with BPh₄⁻. The product could be recrystallised from CH₂Cl₂/MeOH.

EXAMPLE 4

[0170] The preparation of [Tc(NNPh)₂Cl(PPh₃)₂]

[0171] Dry distilled MeOH (5 cm³) was added to a reaction flaskcontaining a magnetic stirring bar, 222 mg PPh₃ (0.85 mmol) and 70 mg[NBu₄][TcOCl₄] (0.14 mmol). This gave an orange suspension containingundissolved PPh₃. After five minutes 0.60 cm³ of PhNHNH₂ (6.1 mmol) wasadded and the reaction mixture was heated to reflux for one hour. Thesolution was cooled to room temperature overnight and the resultantyellow-gold precipitate was collected, washed with MeOH (5 cm³) and Et₂O(10 cm³). The yield of Tc(NNPh)₂Cl(PPh₃)₂, after drying in vacuo, was 94mg (0.11 mmol, 80%) based on technetium. This material is only partiallysoluble in halogenated solvents and insoluble in alcohols. Hence,attempts to purify the complex were only partially successful. Analysiscalculated for C₄₈H₄₀ClN₄P₂Tc: 66.32% C; 4.64% H; 6.45% N. Found: 64.23%C; 4.28% H; 4.87% N.

EXAMPLE 5

[0172] The preparation of [Tc(NNPh)Cl(dppe)₂][PF₆]

[0173] Method 1

[0174] 52 μl of PhNHNH₂ (0.53 mmol) was added to a stirred solution of80 mg [NBu₄][TcOCl₄] (0.16 mmol) in 5 cm³ MeOH. After five minutes 253mg of dppe (0.64 mmol) was added as a solid to the stirred reactionmixture and this was then heated to reflux for one hour. The solutionwas cooled to room temperature, filtered, and an excess of NH₄PF₆ (1 g)in 3 cm³ water was added to precipitate an orange compound. This wascollected, washed with MeOH (15 cm³) and Et₂O (30 cm³), and dried in theair. This gage 95 mg of product (0.08 mmol, 50%). The complex could berecrystallised from CH₂Cl₂/EtOH. Analysis calculated forC₅₈H₅₃ClF₆N₂P₅Tc: 58.97% C; 4.61% H; 2.37% N. Found: 58.92% C; 4.68% H;2.70% N.

[0175] Method 2

[0176] A methanolic solution of [NH₄][TcO₄] was prepared by adding 0.50cm³ of a 0.29 M aqueous solution of [NH₄][TcO₄] (0.15 mmol) to 3.0 cm ofreagent grade MeOH. Phenyl hydrazine (50 μl, 0.51 mmol) was then addedto this stirred solution. No reaction appeared to take place until 0.1cm³ of concentrated HCl was added to the reaction mixture five minuteslater. This was immediately followed by the addition of 241 mg dppe(0.81 mmol) as a solid. The reaction mixture was heated to reflux forone hour, cooled to room temperature and filtered to remove excess,unreacted dppe. An excess of [NH₄][PF₆] was added to the stirredsolution as a solid and the resultant suspension was stirred at roomtemperature overnight. The orange precipitate was then collected, washedwith ^(i)PrOH and Et₂O and dried in vacuo to give 108 mg of[Tc(NNPh)(dppe)₂Cl][PF₆] (0.09 mmol, 60%). The product was identified bycomparison of its IR and ¹H NMR spectra with those obtained from anauthentic sample prepared by Method 1.

EXAMPLE 6

[0177] The Preparation of [Tc(NNC₆H₄Cl)(dppe)₂Cl][PF₆].

[0178] This complex was prepared according to Method 2 above from[NH₄][TcO₄] (0.19 mmol), 129 mg trans-ClC₆H₄NHNH₂.HCl (1.07 mmol) , 0.1cm³ concentrated HCl, and 561 mg dppe (1.41 mmol). Yield of[Tc(NNC₆H₄Cl) (dppe) Cl₂Cl][PF₆]: 298 mg, 0.24 mmol, 84%. Analysiscalculated for C₅₈H₅₂Cl₂F₆N₂P₅Tc. ½ CH₂Cl₂: 55.99% C; 4.25% H; 2.23% N.Found: 55.73 C; 4.37% H; 1.93% N.

EXAMPLE 7

[0179] The reaction of [NBu₄][TcOCl₄] with Benzoylhydrazine and PPh₃

[0180] This reaction was performed according to the Method 1 above forthe synthesis of Tc(NNPh)₂Cl(PPh₃)₂ using 77 mg [NBu₄][TcOCl₄], 70 mgPhC[O]NHNH₂ (0.51 mmol) and 135 mg PPh₃ (0.51 mmol). After the reactionsolution had been heated to reflux for one hour and cooled to roomtemperature, a light orange compound precipitated and was collected,washed with MeOH (15 cm³) and Et₂O (30 cm³) and then dried in the air.The compound was identified as TcNCl₂(PPh₃)₂ by comparison of its IR andNMR spectroscopic characteristics with those of an authentic sample.⁸The yield was 97 mg (0.14 mmol, 88%). Analysis calculated forC₃₆H₃₀Cl₂NP₂Tc: 61.12% C; 4.27% H; 1.98% N. Found: 60.66% C; 4.35% H;2.32% N.

EXAMPLE 8

[0181] The reaction between [NBu₄][TcOCl₄], Benzoylhydrazine and dppe

[0182] This reaction was performed according to Method 1 above using 119mg [NBu₄][TcOCl₄] (0.24 mmol), 91 mg PhC[O]NHNH₂ (0.67 mmol), and 323 mgdppe (0.81 mmol). The cooled reaction solution was filtered and anexcess of [NH₄][PF₆] was added with stirring. THe orange complex wasidentified as [TcN(dppe)₂Cl][PF₆] by comparison of its spectroscopicproperties with those of an authentic sample.²¹

[0183] Yield: 196 mg (0.18 mmol, 75%). Analysis calculated forC₅₂H₄₈ClF₆NP₅Tc: 57.28% C; 4.44% H; 1.28% N. Found: 56.72% C; 4.84% H;0.87% N.

EXAMPLE 9

[0184] The reaction between [NBu₄][TcOCl₄], H₂NNH₂ and dppe

[0185] This reaction was performed by Method 1 above using 124 mg[NBu₄][TcOCl₄] (0.25 mmol), 15 μl H₂NNH₂ (Aldrich, Anhydrous, 0.47 mmol)and 421 mg dppe (1.06 mmol). The reaction solution was heated to refluxfor 30 minutes, cooled to room temperature, filtered and an excess of[NH₄][PF₆] was added to the filtrate with stirring. The resultantorange-brown compound was collected by filtration. Yield: 144 mg (0.20mmol, 80%). This product was identified as the complex[TcN(dppe)₂Cl][PF₆].

EXAMPLE 10

[0186] The Synthesis of TcNNPhMe(PPh₃)₂Cl₃

[0187] 108 mg [NBu₄][TcOCl₄] (0.22 mmol) was dissolved in 10 cm³ dryMeOH and 52 μl MePhNNH₂ (0.44 mmol) was added to the stirred solution.The solution changed from pale green to red-orange immediately. 211 mgPPh₃ (0.80 mmol) was added to the reaction solution and the resultingsuspension was heated to reflux for one hour. The resulting suspensionwas cooled to room temperature and a large amount of a tan precipitatewas collected, washed with MeOH (15 cm³) and Et₂O (30 cm³), and thendried in vacuo. The yield was 108 mg of a complex identified as[Tc(NNPhMe)Cl₃(PPh₃)₂] (0.13 mmol, 59%) Analysis calculated forC₄₃H₃₈C₃N₂P₂Tc: 60.82% C; 4.51% H; 3.30% N; 12.53% Cl. Found: 60.01% C;4.17% H; 3.53% N; 12.20% Cl.

EXAMPLE 11

[0188] The Preparation of [Tc(NNPhMe)Cl₂(PMe₂Ph)₃][PF₆]

[0189] A red-orange solution was prepared by adding 0.10 cm³ MePhNNH₂(0.85 mmol) to a stirred solution of 1.47 mg [NBu₄][TcOCl₄] (0.30 mmol)in 4.0 cm³ of MeOH. 0.20 cm³ of PMe₂Ph was then added to the reactionmixture and this was then heated to reflux for 45 minutes to give aclear orange solution. The solution was then concentrated toapproximately 2 cm³ and then 94 mg [NH₄][PF₆] was added as a solid tothe stirred reaction mixture. The precipitate which formed was collectedand washed with 7:1 (v/v) Et₂O—^(i)PrOH. The filtrate was reconcentratedto give a second crop of gold-brown microcrystalline material. The yieldwas 138 mg of [Tc(NNMePh)Cl₂(PMe₂Ph)₃][PF₆] (0.16 mmol, 54%). Analysiscaluclated for C₃₁H₄₀Cl₂F₆N₂P₄Tc: 43.93% C; 4.76% H; 3.31% N. Found:44.53% C; 5.22% H; 3.10% N.

EXAMPLE 12

[0190] The Preparation of [Tc^(V)(NNPhMe)Cl(Et₂NCS₂)₂]

[0191] A red-orange solution was prepared as described above from 138 mg[NBu₄][TcOCl₄] (0.28 mmol) and 80 μl MePhNNH₄H₂ (0.68 mmol) in 3 cm³ ofMeOH. After this solution had been stirred at room temperature for fiveminutes, a solution of 200 mg NaS₂CNEt₂.3H₂O (0.89 mmol) in 2 cm³ MeOH.The resulting dark red solution was heated to reflux for 30 minutes,cooled to room temperature and the solvent was removed in vacuo to givea red, oily residue. This residue was taken up in 5 cm³ of ^(i)PrOH andthis suspension was filtered to give 73 mg of a pale brown powder whichwas washed with Et₂O. The filtrate was concentrated to about 1-2 cm³volume and 50 cm³ Et₂O was added. The precipitated thus formed wascollected and identical to the original material isolated. The overallyield of the complex, identified as [Tc(NNMePh)Cl(Et₂NCS₂)₂] was 111 mg(0.02 mmol, 71%). The complex could be recrystallised from CH₂Cl₂/Et₂O.Analysis calculated for C₁₇H₂₇ClN₄S₄Tc: 37.12% C; 4.95% H; 10.19% N;6.44% Cl. Found: 38% C; 5% H; 11% N; 9.4% Cl.

EXAMPLE 13

[0192] The Reaction between [NBu₄][TcOCl₄], MePhNNH₂ and dppe

[0193] An orange solution was prepared as described above from 100 mg[NBu₄][TcOCl₄] (0.20 mmol), 45 μl MePhNNH₂ (0.38 mmol) in 4 cm³ MeOH.550 mg dppe (1.38 mmol) was then added to this stirred solution as asolid and the resultant suspension was heated to reflux for one hour,cooled to room temperature and filtered to remove unreacted dppe. Anexcess of [NH₄][PF₆] was added as a solid to the filtered solution togive a tan precipitate which was washed with MeOH (20 cm³) and Et₂O (10cm³). This yielded 121 mg of [Tc(NH)O(dppe)₂][PF₆] (0.11 mmol, 55%).Analysis calculated for C₅₂H₄₉F₆NOP₅Tc: 58.27% C; 4.61% H; 1.31% N.Found: 56.90% C; 4.70% H; 1.61% N.

EXAMPLE 14

[0194] The Reaction of [NBu₄][TcOCl₄], Me₂NNH₂ and dppe

[0195] Method 1

[0196] An orange-red solution was prepared as described above from 211mg [NBu₄][TcOCl₄] (0.42 mmol), 35 μl Me₂NNH₂ (0.46 mmol) in 5 cm³ MeOHand then 366 mg dppe (1.40 mmol) was added as a solid. The reactionmixture was heated to reflux for one hour, cooled to room temperatureand a yellow precipitate was collected (72 mg of [Tc(N₂) (dppe)₂Cl](0.07 mmol, 17%). An excess of [NH₄][PF₆] was added as a solid to thefiltrate to give a gold-brown precipitate (137 mg) of[Tc(NNMe₂)Cl(dppe)₂][PF₆] (0.12 mmol, 29%).

[0197] For [Tc(N₂) (dppe) Cl]

[0198] Analysis calculated for C₅₂H₄₈ClN₂P₄Tc: 65.17% C; 5.05% H; 2.92%N. Found: 64.70% C; 5.32% H; 2.07% N.

[0199] For [Tc(NNMe₂)Cl(dppe)₂][PF₆]

[0200] Analysis calculated for C₅₄H₅₂ClF₆P₅Tc: 57.33% C; 4.63% H; 2.48%N. Found: 51.6% C; 4.4% H; 1.8% N.

[0201] Method 2

[0202] A reaction solution was prepared as for Method 1 from 95 mg[NBu₄][TcOCl₄] (0.19 mmol), 27 μl Me₂NHH₂ (0.36 mmol), 333 mg dppe (0.84mmol) in 5 cm³ MeOH. This reaction mixture was stirred at roomtemperature for 70 hours. The reaction solution was filtered to removeexcess dppe (no yellow precipitate was observed), 65 mg NH₄PF₆ (0.40mmol) was added to the filtrate as a solid and the solution was thenconcentrated in vacuo and the residue was taken up in 5 cm³ CH₂Cl₂. Thissolution was filtered to remove undissolved inorganic salts. Afterfiltration, 25 cm³ ^(i)PrOH was added to the filtrate to give 135 mg ofa yellow-brown solid which was collected, washed and dried. This wasidentified by comparison of the IR spectrum of this complex with that of[Tc(NNMe₂)Cl(dppe)₂][PF₆] prepared by Method 1 (0.12 mmol, 63%).

EXAMPLE 15

[0203] The Reaction of [NBu₄][TcOBr₄], Me₂NNH₂ and dppe

[0204] This was performed by Method 1 for the reaction described abovefor [NBu₄][TcOCl₄] using 130 mg [NBu₄][TcOBr₄] (0.20 mmol), 20 μlMe₂NNH₂ (0.26 mmol), 247 mg dppe (0.62 mmol) in 5 cm³ MeOH. This gave 55mg of a yellow complex, Tc(N₂)Br(dppe)₂ (0.06 mmol, 30%). No salts wereisolated from the reaction filtrate after the addition of an excess ofNH₄PF₆ to the solution. Analysis calculated for C₅₂H₄₈BrN₂P₄Tc: 62.22%C; 4.82% H; 2.79% N. Found: 58.48% C; 4.71% H; 2.03% N.

[0205]^(99m)Tc Complexes

[0206] General: The ^(99m)Tc diazenide and hydrazide (2−) complexes wereprepared in a straightforward fashion from the appropriate hydrazine,^(99m)TcO₄ ⁻ and a suitable ligand. The complex preparations were foundto yield the desired cationic products in reasonably high radiochemicalpurity (see Tables 2-4). The main contaminants in these preparationswere the [Tc^(III)Cl₂(L)₂]⁺ cations, as verified by comparison of HPLCand TLC characteristics of these impurities with authentic samples ofthese Tc^(III) species prepared by a literature method.²² There is somequestion in the case of the MePhNNH₂ labelled species whether thecomplexes formed are of the formulation [Tc^(IV)(NNMePh)Cl(L)₂]⁺ or[Tc^(V)(NH)O(L)₂]⁺. Recent ICES studies on the preparation obtained fromthe labelling where L=P65 (mmmpe) have shown that the oxidation state ofthe complex obtained is +4.²³ This indicates that the species present inthe MePhNNH₂ preparations are the desired hydrazido (2−) species.

[0207] Reagents: The ligands used are given in Table 1. All otherreagents used were from commercial suppliers and used as received.^(99m)TcO₄]⁻ was obtained as solutions in physiological saline fromAmertec II generators. Reaction products were analyzed by HPLC, TLC andgel electrophoresis as described elsewhere.²⁴ All preparations wereperformed under an atmosphere of nitrogen gas.

EXAMPLE 16

[0208] Complex Preparation: 20-25 μl of hydrazine was added to 2 cm³ ofabsolute ethanol, then ^(99m)TcO₄ ⁻ (0.2-3.0 GBq) and 10 mg of ligandwere added to the solution. This mixture was heated to 120° C. for 30-60minutes, cooled to room temperature and analyzed. For biodistributionstudies the total volume of the preparation was made up to 5 cm³ by theaddition of sterile saline solution.

[0209] Animal Biodistribution Studies: Six male Sprague Dawley rats wereinjected while under light ether anaesthesia with 0.1 cm³ of preparation(i.v., tail vein) and half were sacrificed by cervical dislocation whileunder ether anaesthesia at the appropriate time interval post-infectionand dissected. Organs were weighed and their activities measured in anionisation chamber. For the purposes of calculations blood was assumedto constitute 5.8% of the total body weight, muscle was assumed to be43% and the lungs were assumed to weigh 1 g.

[0210] Biodistribution results are given in Tables 2-4. TABLE 1 Ligandsused in ^(99m)Tc labelling work Abbreviation Structure Name dmpe

1,2-bis(dimethylphosphino)ethane dppe

1,2-bis(diphenylphosphino)ethane P56

1,2-bis(di(3-methoxypropyl) phosphino)ethane PL28

bis((dimethylphosphino)methyl)ether P46

1,2-bis((2′-methoxy)ethoxymethyl) methylphosphino)ethane PL34

1,3-bis(dimethylphosphino)-2- ((2-methoxy)ethoxy)propane PL38

1-3-bis(dimethylphosphino)-2,2-bis (2-(2-ethoxy)ethoxy)ethoxymethyl)propane; or 1,3-bis(dimethylphosphino)-2,2-bis(2,5,8-trioxadecyl)propane PL31

bis((diethylphosphino)methyl)ether P53

1,2-bis(di(2′-ethoxy)ethyl)phosphino ethane P65

1,2-bis((methoxymethyl)methyl phosphine)ethane PL37

1,3-bis(dimethylphosphine)-2,2-bis (methoxymethyl)propane PL40

1,3-bis(dimethylphosphino)-2,2-bis (2′,5′-dioxaheptyl)propane PL42

1,3-bis(dimethylphosphino)-2,2-bis (ethoxymethyl)propane PL43

1,3-bis(dimethylphosphino)-2,2-bis ((2′-methoxy)ethoxymethyl) propanePL46

1,3-bis(dimethylphosphino)-2- (methoxymethol)-2-((2′-methoxy)ethoxymethyl)propane PL49

4,4-bis((dimethylphosphino)methyl) tetrahydropyran PL50

1,3-bis(dimethylphosphino)-2,2-bis (methoxyethyl)propane P68

1,2-bis(di((2′methoxy)propyl) phosphino)ethane

[0211] TABLE 2 Biodistributions of Phenyldiacenide ^(99m) Tc species inRats Notebook IV23 VI12 V19 Ligand dmpe PL28 P46 MEK 60 84 80 RCP (%)HPLC 40 70 75 Time P.I. 2 60 2 60 2 60 Heart 0.91 (14) 0.78 (03) 1.12(11) 0.65 (06) 0.96 (04) 0.80 (02) Blood 6.98 (71) 1.10 (02) 4.18 (05)0.46 (04) 7.45 (63) 1.01 (16) Muscle 22.8 (3.0) 14.0 (3.7) 30.2 (3.0)27.4 (3.6) 21.4 (3.1) 17.0 (4.0) Lung 1.88 (14) 0.86 (10) 1.18 (14) 0.62(05) 1.41 (27) 0.36 (05) Liver 22.2 (2.6) 10.5 (8) 17.8 (2.9) 5.95 (57)26.0 (1.0) 6.92 (1.23) S.I. 13.2 (8) 36.7 (4) 13.2 (1.0) 39.6 (2.7) 11.0(3.2) 44.0 (1.9) Kidney 11.2 (8) 9.91 (1.25) 9.41 (0.30) 5.90 (06) 9.62(48) 2.88 (16) Bladder & 0.11 (03) 11.3 (4) 0.11 (06) 10.9 (5.9) 0.11(05) 17.8 (2.6) Urine Brain 0.06 (01) 0.02 (01) 0.04 (00) 0.02 (00) 0.05(01) 0.01 (00) H/Bl 1.97 (05) 9.52 (33) 3.97 (32) 21.3 (0.8) 2.05 (29)13.2 (2.1) H/Li 0.54 (11) 0.93 (11) 0.82 (19) 1.56 (12) 0.58 (06) 1.79(30) Notebook VI31 LH2.17 LH2.30 Ligand P46 (HPLC purified) PL42 PL43MEK 50 65 26 RCP (%) HPLC 50 70 50 Time P.I. 2 60 2 60 2 60 Heart 1.05(09) 0.96 (04) 1.22 (30) 1.19 (20) 0.55 (03) 0.26 (03) Blood 7.00 (0.31)0.78 (08) 28.6 (1.4) 8.99 (2.28) 21.5 (3.5) 1.14 (36) Muscle 21.0 (3.1)21.3 (2.3) 18.1 (0.5) 21.3 (0.3) 21.7 (2.4) 10.9 (1.3) Lung 1.33 (14)0.17 (05) 2.56 (33) 1.57 (32) 1.47 (04) 0.22 (03) Liver 22.1 (2.0) 4.94(77) 22.8 (3.2) 14.7 (1.6) 21.4 (1.6) 9.08 (2.03) S.I. 11.5 (3.2) 39.8(0.3) 7.66 (18) 31.8 (2.0) 8.6 (0.5) 45.6 (6.8) Kidney 11.1 (2.1) 3.31(17) 5.35 (46) 3.52 (47) 9.19 (74) 2.32 (32) Bladder & 1.01 (1.49) 17.0(4.3) 0.06 (01) 2.61 (23) −0.16 (06) 25.4 (4.6) Urine Brain 0.04 (00)0.01 (00)   —   —   —   — H/Bl 2.37 (12) 18.9 (1.6) 0.59 (12) 2.13 (43)0.41 (06) 3.83 (1.03) H/Li 0.66 (12) 2.77 (36) 0.73 (24) 1.12 (26) 0.38(03) 0.40 (03) Notebook LH2.51 PAH1.26 VI28 Ligand P65 PL50 PL38 MEK 6070 86 RCP (%) HPLC 85 75 80 Time P.I. 2 60 2 60 2 60 Heart 1.20 (11)1.08 (09) 0.83 (09) 0.65 (04) 1.04 (06) 0.65 (09) Blood 5.73 (58) 1.05(09) 4.38 (25) 0.42 (03) 4.51 (1.36) 0.16 (02) Muscle 27.8 (8.1) 23.6(7.7) 18.7 (2.5) 14.9 (2.7) 21.0 (5.1) 16.2 (4.1) Lung 1.61 (18) 0.53(08) 1.02 (12) 0.43 (06) 1.41 (13) 0.35 (11) Liver 22.0 (1.8) 6.68(1.19) 34.8 (1.2) 4.35 (30) 28.4 (1.6) 9.27 (35) S.I. 11.2 (2.1) 39.8(4.3) 12.8 (0.7) 57.9 (2.4) 11.5 (2.0) 57.0 (2.8) Kidney 12.0 (1.2) 3.71(07) 12.0 (0.30) 6.81 (56) 10.7 (1.9) 4.01 (44) Bladder & 0.11 (0.05)9.95 (66) 0.09 (03) 6.76 (65) 0.14 (04) 5.81 (1.46) Urine Brain   —   —  —   — 0.63 (00) 0.00 (00) H/Bl 3.33 (30) 15.8 (1.0) 2.68 (22) 22.2(0.4) 3.59 (88) 62.5 (7.0) H/Li 0.81 (12) 2.33 (32) 0.31 (04) 1.27 (96)0.48 (01) 1.05 (17)

[0212] TABLE 3 Biodistributions of [Tc^(III)(NNC₆H₄NO₂)(Cl(dmpe)₂]⁺ inRats Notebook CMAIV78 Ligand dmpe MEK 86 RCP (%) HPLC 65 Time P.I. 2 60Heart 1.15 (22) 0.67 (05) Blood 5.68 (66) 0.92 (07) Muscle 26.2 (7.7)16.8 (1.2) Lung 2.27 (15) 1.04 (23) Liver 22.4 (3.9) 12.3 (0.7) S.I.13.0 (3.1) 33.8 (3.2) Kidney 9.47 (25) 9.47 (33) Bladder 0.08 (02) 7.28(1.10) & Urine Brain 0.12 (00) 0.06 (00) H/B1 3.00 (49) 11.0 (0.9) H/L10.72 (28) 0.76 (12)

[0213] TABLE 4 Biodistributions of ^(99m)Tc-hydrazide (2-) species inRats and Guinea Pigs Notebook PAH2.14 CMAIV58 CMAV141 Ligand P65 dmpedmpc (HPLC purified) MEK 86 78 83 RCP (%) HPLC 90 70 73 Time P.I. 2 60 260 2 60 Heart 0.95 (09) 0.69 (03) 1.13 (13) 0.80 (08) 1.25 (08) 0.99(15) Blood 4.77 (10) 0.69 (13) 7.84 (47) 1.05 (11) 7.95 (21) 1.05 (21)Muscle 26.1 (5.8) 20.2 (2.7) 27.9 (4.9) 20.6 (3.2) 26.3 (5.2) 19.3 (4.9)Lung 1.58 (0.36) 0.33 (02) 2.36 (37) 1.14 (07) 2.40 (0.21) 1.28 (20)Liver 22.8 (1.4) 9.23 (26) 22.2 (0.6) 11.6 (1.6) 21.1 (1.7) 10.8 (1.9)S.I. 10.5 (2.2) 30.6 (3.4) 11.9 (3.2) 31.1 (4.5) Kidney 7.76 (12) 1.95(15) 9.95 (1.40) 11.1 (0.4) 10.8 (0.6) 11.6 (1.3) Bladder & 0.08 (01)6.84 (77) 0.12 (07) 4.70 (93) Urine Brain 0.05 (01) 0.03 (01) 0.07 (01)0.04 (01) H/Bl 3.25 (27) 15.0 (3.4) 2.43 (12) 12.2 (1.4) 2.27 (21) 14.2(2.4) H/Li 0.64 (06) 1.11 (02) 0.78 (13) 1.06 (13) 0.82 (04) 1.30 (41)Notebook CMAVI15 CMAVI36 CMAVI36 Ligand P46 P46* (HPLC purified) P46(HPLC purified) RATS MEK 64 54 54 RCP (%) HPLC 65 53 53 Time P.I. 2 60 260 60 Heart 0.81 (07) 0.58 (04) 0.96 (12) 0.65 (03) 0.97 (06) Blood 7.10(0.51) 0.50 (05) 10.1 (1.7) 0.89 (12) 0.27 (02) Muscle 28.4 (2.5) 18.4(2.5) 21.9 (3.3) 28.5 (2.2) 20.0 (1.2) Lung 1.33 (09) 0.30 (07) 1.30(05) 0.51 (11) 0.36 (10) Liver 23.3 (0.5) 7.23 (70) 15.9 (1.1) 5.18 (36)8.29 (67) S.I. 9.38 (3.20) 44.8 (2.6) 11.3 (1.2) 15.0 (7.1) 43.6 (2.2)Kidney 9.37 (52) 2.13 (10) 13.0 (1.6) 11.0 (0.3) 4.05 (66) Bladder &0.18 (10) 19.2 (1.6) 0.22 (17) 10.6 (1.1) 12.7 (1.0) Urine Brain 0.04(02) 0.51 (13)   —   —   — H/Bl 1.65 (08) 16.5 (1.0) 2.89 (53) 17.8(2.1) 58.7 (7.0) H/Li 0.48 (03) 1.01 (13) 0.88 (10) 1.89 (0.22) 1.68(14)

EXAMPLES 17-19

[0214] All reactions were performed under an atmosphere of dinitrogenusing predried, distilled solvents unless noted otherwise.[Bu₄N][TcOCl₄] was prepared by the literature procedure.²⁸

EXAMPLE 17

[0215] Technetium Diazenido-Starting Materials

[0216] a) [TcCl(NNC₆H₄Cl)₂(PPh₃)₂]9

[0217] Method 1. From [Bu₄N][TcOCl₄]

[0218] [Bu₄N][TcOCl₄] (0.134 g, 0.268 mmol), 4-ClC₆H₄NHNH₂.HCl (0.120 g,0.67 mmol, 2.5 equivalents), Et₃N (0.09 ml, 0.67 mmol), and PPh₃ (0.211g, 0.804 mmol , 3 equivalents) in dry methanol (5 ml) were stirred for 2hours at room temperature. The khaki solid was collected by filtration,washed with methanol and ether and dried. (yield 0.134 g, 53%). Theproduct could be recrystallised from CH₂Cl₂/MeOH yielding bright orangecrystals. (Found: C, 61.23; H, 3.98; N, 6.05; Cl, 11.74. TcC₄₈H₃₈N₄P₂Cl₃requires C, 61.45; H, 4.08; N, 5.97; Cl, 11.34%). HPLC retention time9.4 minutes, single species. v_(max). (KBr plates, nujol mull) 1600,1555 cm⁻¹ (NN). ³¹P NMR (CDCl₃) 30.27 ppm singlet.

[0219] Method 2. From [NH₄][TcO₄]

[0220] Aqueous [NH₄][TcO₄] (0.5 ml, 0.181 mmol) was evaporated todryness in vacuo. ClC₆H₄NHNH₂.HCl (0.142 g, 0.793 mmol) in dry methanol(2.5 ml) was added with stirring to give an orange solution after 10minutes. Solid PPh₃ (0.204 g, 0.778 mmol) was added and the mixtureheated under reflux for 1.5 hours. After cooling to room temperature thekhaki solid was collected by filtration and washed with ether (yield0.113 g, 67%). The product could be crystallised from CH₂Cl₂/MeOH toyield an orange crystalline solid which has an identical IR spectrum toan authentic sample of 9 prepared from [TcOCl₄]⁻.

[0221] b) [Tc(NNC₆H₄CH₃)₂(PPh₃)₂]10

[0222] [Bu₄N][TcOCl₄] (0.178 g, 0.356 mmol), CH₃C₆H₄NHNH₂.HCl (0.282 g,1.78 mmol, 5 equivalents), Et₃N (0.25 ml, 1.78 mmol), and PPh₃ (0.280 g,1.07 mmol, 3 equivalents) were stirred in dry methanol (5 ml) overnightto give a khaki suspension. The product was collected by filtration,washed with ether and dried (yield 0.122 g, 40%). HPLC retention time10.4 minutes, one major species. Analysis on the crude material gave(Found: C, 64.1; H, 4.6; N, 5.9; Cl, 3.53. TcC₅₀H₄₄N₄P₂Cl requires C,66.93; H, 4.94; N, 6.24; Cl, 3.95%). ¹H NMR (CDCl₃) 2.29[6H, s, 2×CH₃],6.5-8.0 [38H, m, phenyl H]. ³¹P NMR (CDCl₃) 28.6 ppm singlet. v_(max).1620, 1570, 1535 cm⁻¹ (NN). The product may be recrystallised fromCH₂Cl₂/MeOH.

[0223] c) [TcCl₂(NNC₆H₄NO₂)(PPh₃)₂]11

[0224] [Bu₄N[TcOCl₄] (0.152 g, 0.304 mmol), O₂NC₆H₄NHNH₂ (0.116 g, 0.76mmol, 2.5 equivalents), and PPh₃ (0.239 g, 0.912 mmol, 3 equivalents) indry methanol (5 ml) were stirred overnight to give a pale orange solidwhich was collected by filtration (yield 0.223 g, 77%). This wasrecrystallised from CH₂Cl₂/MeOH to give a lime-green solid (0.151 g,52%). v_(max). 1620, 1600 (NN), 1555 (NO₂), 1335 (NO₂) cm⁻¹.

[0225]¹H NMR (CDCl₃) 3.4 [MeOH], 7.0-8.0[phenyl H]. ³¹ P NMR (CDCl₃)30.0 ppm singlet. HPLC retention time 10.4 minutes. (Found: C, 57.65;H,4.18; N, 4.94; Cl, 8.60. Found: C, 57.42; H, 4.24; N, 4.95; Cl, 7.95.TcC₄₃H₃₈N₃Cl₂O₃P₂ requires C, 58.92; H, 4.37; N, 4.79; Cl, 8.09%).

EXAMPLE 18

[0226] Substitution Chemistry of the Technetium Diazenido-StartingMaterials

[0227] a) [TcCl(NNC₆H Cl)(dppe)₂][BPh₄]12

[0228] 9 (0.098 g, 0.104 mmol) and dppe (0.104 g, 0.26 mmol, 2.5equivalents) in methanol-toluene (1:1, 4 ml) were heated under refluxfor 3 hours to give a dark orange solution. Solid NaBPh₄ (0.035 g, 1equivalent) was added with stirring to precipitate an orange solid. Theproduct was collected by filtration (yield 0.117 g, 77%). The crudeproduct could be recrystallised from CH₂Cl₂/ether. (Found: C, 70.55; H,5.34; N, 2.17; Cl, 4.72. TcC₈₀H₇₂N₂BP₄Cl₂ requires C, 70.34; H, 5.31; N,2.05; Cl, 5.19%). HPLC retention time 14 minutes. v_(max). 1575, 1665cm⁻¹ (NN). ¹H NMR (CDCl₃) 2.68 [8H, broad m, 2×—CH₂CH₂—], 6.5-7.5[64H,broad unresolved m, phenyl H].

[0229] b) [TcCl(NNC₆P Cl) (dppe)₂][PF₆]12a

[0230] This was prepared in an analogous fashion to 12 using 9 (0.101 g,0.107 mmol) and dppe (0.107 g, 0.269 mmol) in methanol/toluene (1:1, 4ml) under reflux for 1 hour. [NH₄][PF₆] (0.018 g, 0.110 mmol) was addedwith stirring to the filtered reaction mixture to give 12a (yield 0.059g, 43%). This could be recrystallised from CH₂Cl₂/MeOH (Found: C, 55.44;H, 4.27; N, 2.48; Cl, 6.35. TcC₅₈H₄₄N₂P₅Cl₂F₆ requires C, 57.68; H,3.67; N, 2.32; Cl, 5.87%).

[0231] c) [TcCl(NNC₆H₄NO₂)(dppe)₂][BPh₄]13

[0232] 11 (0.051 g, 0.06 mmol) and dppe (0.060 g, 0.151 mmol, 2.5equivalents) in methanol/toluene (1:1, 3 ml) were heated under refluxfor 1 hour to give an orange-red solution. After cooling to roomtemperature solid NaBPh₄(0.02 g, 1 equivalent) was added with stirringto precipitate the product as an orange solid. This was collected byfiltration and washed with MeOH and Et₂O (yield 0.06 g, 72%). Theproduct was recrystallised from CH₂Cl₂/Et₂O (yield 0.042 g, 50%) as anorange crystalline solid. v_(max). 1645s, 1600w (NN), 1570 (NO₂), 1340(NO₂) cm⁻¹. HPLC retention time 14.2 minutes, single peak. (Found: C,67.65; H, 5.12; N, 2.93; Cl, 4.14. TcC₈₂H₇₂N₃O₂Cl—P₄B.½CH₂Cl₂ requiresC, 68.66; H, 5.10; N, 2.91; Cl, 4.91%).

[0233] d) [Tc(NNC₆H₄Cl)(S₂CNMe₂)₂(PPh₃)]14

[0234] 9 (0.139 g, 0.148 mmol) and NaS₂CNMe₂ (0.08 g, 0.444 mmol, 3equivalents) in absolute ethanol (2 ml) were heated under reflux for 1.5hours. The orange solid was collected by filtration after cooling (yield0.072 g) and redissolved in CH₂Cl₂ before passage down a Fluorsil columneluting the orange band with CH₂C₂. This eluate was evaporated todryness and the residue recrystallised from CH₂Cl₂/Et₂O to give darkorange crystals (yield 0.072 g, 66%). HPLC retention time 13.6 minutes,single species. (Found: C, 45.82; H, 4.09; N, 6.79; Cl, 6.25. Found: C,45.99; H, 4.04; N, 6.77. TcC₃₀H₃₁N₄ClS₄P.½CH₂C₂ requires C, 46.74; H,4.11, N, 7.15; Cl, 9.05. TcC₃₀H₃₁N₄ClS₄P.¼CH₂Cl₂ requires C, 47.65; H,4.16, N, 7.35; Cl 6.97%). ¹H NMR (CDCl₃) 2.92[3H, s, CH₃], 3.06[3H, s,CH₃], 3.31[3H, s, CH₃], 3.39[3H, s, CH₃], 5.27[CH₂CH₂], 6.8-7.7[19H, m,phenyl H]. ³¹P NMR (CDCl₃) no signal was observed in this sample at roomtemperature.

[0235] e) [TcCl(NNC₆H₄Cl) (maltol) (PPh₃)₂]15

[0236] 9 (0.145 g, 0.155 mmol) and maltol (0.059 g, 0.465 mmol, 3equivalents) in absolute ethanol (2 ml) were heated under reflux for 2hours. After cooling to room temperature the orange product wascollected by filtration and washed with ethanol. The product wasrecrystallised from CH₂ C₂/ether (yield 0.03 g, 21%) as dark orangecrystals. (Found: C, 59.68; H, 4.11; N, 3.03; Cl, 7.73.TcC₄₈H₃₉N₂Cl₂O₃P₂ requires C, 62.41; H, 4.23; N, 3.03, Cl, 7.68%).v_(max). 1615s, 1560 cm⁻¹. ¹H NMR (CDCl₃) 2.21[3H, s, CH₃], 5.63[1H, d,J³ _(HH)=4 Hz, C═CH], 6.92[1H, d, J³ _(HH)=4 Hz, C═CH], 7.0-8.0[34H, mphenyl H]. ³¹P NMR (CDCl₃) 30.0 ppm singlet. HPLC retention time 10minutes.

[0237] f) [Tc(NNC₆H₄Cl)(salen)(PPh₃)]16

[0238] 9 (0.100 g, 0.107 mmol), salenH₂ (0.032 g, 0.119 mmol, 1.1equivalents), and Et₃N (0.40 ml, 0.259 mmol, 2.2 equivalents) in drymethanol/toluene (1:1, 3 ml) were heated under reflux for 2 hours. Aftercooling, addition of ether gave a khaki-green solid which was collectedby filtration, washed with ether and dried (yield 0.052 g, 63%). Theproduct could be recrystallised from CH₂Cl₂/heptane as very dark greencrystals. (Found; C, 61.77; H, 4.41; N, 7.17; Cl, 4.77. TcC₄₀H₃₃N₄PO₂Clrequires C, 62.63; H, 4.34; N, 7.30; Cl, 4.62%). v_(max). 1600, 1610,1620 (NN), 1540 (C═N) cm⁻¹. ¹H NMR (CDCl₃) 4.0[4H, broad m, —CH₂CH₂—],6.0-7.6[27H, broad m, phenyl H], 8.14[2H, s, N═CH]. ³¹P NMR (CDCl₃) nosignal was observed at room temperature. HPLC retention time 11.6minutes.

[0239] g) [Tc(NNC₆H₄Cl)₂(N₂S₂)]_(x)17 N₂S₂═(HSCH(Me)CONHCH₂—)₂

[0240] 9 (0.083 g, 0.088 mmol), N₂S₂ (0.023 g, 0.097 mmol, 1.1equivalents), and Et₃N (0.05 ml, 0.34 mmol, 4 equivalents) in drymethanol (2 ml) were heated under reflux for 1 hour to give a darkbrown-green solution. The solvent was removed in vacuo and the brown oiltriturated with isopropanol to give a dark brown solid product (yield0.011 g). The product was too insoluble for satisfactoryrecrystallisation and analysis by NMR, but appeared to be diamagnetic.HPLC retention time 12.2 minutes. (Found: C,40.36; H, 4.40; N, 9.19; Cl,11.97. TcC₂₀H₂₄N₄Cl₂S₂O₂ requires C, 40.96; H, 4.12; N, 9.55; Cl12.09%).

EXAMPLE 19

[0241] Technetium Imido Complexes

[0242] [TcCl₂(NC₆H₄CO₂)(PPh₃)_(2])18

[0243] Method 1. From [NH₄][TcO₄]

[0244] Aqueous [NH₄][TcO₄] (1 ml, 0.343 mmol), 2—HO₂CC₆H₄NH₃Cl(2-carboxyaniline hydrochloride) (0.298 g, 1.715 mmol, 5 equivalents),and PPh₃ (0.360 g, 1.372 mmol, 4 equivalents) in reagent grade methanol(10 ml) were stirred overnight to give a bright green precipitate. Theproduct was collected by filtration, washed with MeOH, ether and driedin vacuo (yield 0.139 g, 50%). (Found: C, 63.30; H, 4.44; N, 1.77.TcC₄₃H₃₄NO₂P₂Cl₂ requires C, 62.33; H, 4.14; N, 1.67%). The product wassoluble in DMF and CH₂Cl₂,

[0245] Method 2. From [Bu₄N][TcOCl₄]

[0246] [Bu₄N][TcOCl₄] (0.262 g, 0.525 mmol), anthranilic acid (0.72 g,5.25 mmol, 10 equivalents), and PPh₃ (0.48 g, 1.84 mmol, 3.5equivalents) in absolute ethanol (20 ml) were heated under reflux for 2hours. The hot solution was filtered (air) and taken to dryness invacuo. The residue was then triturated with ether and the solid greenproduct isolated after filtration was recrystallised from EtOH/hexane(yield 0.114 g, 26%). ³¹P NMR (DMSO) 31.2 ppm singlet.

REFERENCES

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[0248] 2. Clark, M. J.; Podbielski, L. Coord. Chem. Rev., 1987, 78, 253.

[0249] 3. I. Rothwell in ‘Comprehensive Coordination Chemistry’, Vol 2(eds. G. Wilkinson, R. D. Gillard, and J. A. McCleverty) Pergamon Press(1987)

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[0254] 8. E. A. Maatta, Inorg. Chem., (1984), 23, 2560.

[0255] 9. C. Y. Chou, J. C. Huffman, and E. A. Maatta, J. Chem. Soc.,Chem. Commun., (1984), 1184.

[0256] 10. a.

[0257] Johnson, B. F. G.; Haymore, B. L.; Dilworth J. R. in“Comprehensive Coord. Chem.”, Wilkinson, G.; Gillard, R. D.; McCleverty,J. A., eds.; Pergamon Press: Oxford, 1988.

[0258] b. Nugent, W. A.; Haymore, B. L. Coord. Chem. Rev., 1980, 31,123-175.

[0259] c. Hsieh, T.-C.; Shaikh, S. N.; Zubieta, J. Inorg. Chem., 1987,26, 4079.

[0260] 11. Golton, R.; Tomkins, I. B.; Wilson, P. W. Aust. J. Chem.,1964, 17, 496-7.

[0261] 12. Dilworth, J. R., Morton, S. Transition Met. Chem., 1987, 12,41.

[0262] 13. Moore, F. W.; Larson, M. L. Inorg. Chem., 1967, 6, 988.

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What is claimed is:
 1. A ^(99M)Tc complex which comprises the moietyL_(n)Tc═NR, L_(n)Tc—N═NY or L_(n)Tc(—N═NY)₂, where: L is independently amonodentate or multidentate ligand; R is an aryl group, a substituted orunsubstituted alkyl group or the group —NR¹R² ₁, Y is a substituted orunsubstituted aryl group or a substituted or unsubstituted alkyl group;R¹ and R² are H, aryl groups or substituted or unsubstituted aliphaticor cyclic alkyl groups, and are the same or different provided that bothare not hydrogen, and n is 1, 2, 3 or
 4. 2. A radiopharmaceuticalcomposition which comprises the ^(99m)Tc complex of claim
 1. 3. Theradiopharmaceutical composition of claim 2, wherein the biologicaltarget seeking properties of the ^(99m)Tc complex are determined by theligands present, or the substituents R and Y, or a combination of theligands present and the substituents R and Y.
 4. A method of preparationof the ^(99m)Tc complex of claim 1, which comprises the derivitizationof a technetium oxo-containing species by condensation with a hydrazine,an amine, an isocyanate, a sulphinylamine or a phosphinimine.
 5. Themethod of claim 4 wherein the technetium oxo-containing species is^(99m)Tc-pertechnetate.